In heart failure (HF), bidirectional communication between the heart and other organs, known as metabolic crosstalk, progressively develops and impacts both major clinical outcomes and responses to HF therapies. The interplay between heart and organs, such as liver, adipose tissues, and bones, involves numerous signaling molecules, metabolic substrates, and enzymatic pathways that amplify metabolic crosstalk and further exacerbate cardiac dysfunction. The mechanisms sustaining this phenomenon are reviewed in detail in this chapter, leading to the identification of the most promising diagnostic biomarkers for monitoring metabolic crosstalk in HF and potential therapeutic targets. Currently, the most promising treatment strategies are pharmacological: vericiguat, tirzepatide, semaglutide, SGLT2 inhibitors, and anti-inflammatory drugs are among the most relevant drugs, approved for clinical practice, that present the potential to interfere with the negative effects of propagation of metabolic crosstalk in HF.